Pathway based-approach for analysis of the New Zealand genome-wide association study in abdominal aortic aneurysm

JavaScript is disabled for your browser. Some features of this site may not work without it.

Pathway based-approach for analysis of the New Zealand genome-wide association study in abdominal aortic aneurysm

Yu, Zhuo (Grace)

Cite this item:Yu, Z. (Grace). (2013). Pathway based-approach for analysis of the New Zealand genome-wide association study in abdominal aortic aneurysm (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/3803

Abstract:

Background: Abdominal aortic aneurysm (AAA) is a life-threatening disease with a strong genetic component that predominantly affects elderly males. Previous genome-wide association studies (GWAS) have identified a number of genetic markers with large effects contributing to disease susceptibility. However, the understanding of AAA pathogenesis remains incomplete. This thesis investigated the role of genetic variations in two pathways in the New Zealand AAA GWAS, the transforming growth factor beta (TGF-β) signaling pathway and the combined dyslipidemia/coronary artery disease pathway, to gain more understanding of the biological insights in AAA.

Methods: The New Zealand discovery GWAS was performed using DNA samples from 621 AAA cases and 627 controls matched for age and gender. The Affymetrix genome-wide human single nucleotide polymorphism (SNP) 6.0 arrays were used, and suitable quality control assessments of the resulting genotyping were conducted to raise genotyping accuracy. Candidate genes from each pathway were selected based on either the biological activities (TGF-β pathway) or on previous evidence with risk association in other cardiovascular conditions (dyslipidemia/coronary artery disease pathway). A multi-staged analysis was conducted as putative associations identified in the discovery GWAS were then followed up in an additional New Zealand AAA cohort using Taqman genotype assays. Further replication (in silico) of associations of candidate SNPs with AAA was carried out in additional international AAA populations. The specificity of putative associations with AAA was assessed by adjusting for common cardiovascular risk confounders.

Results: The New Zealand AAA achieved an average genotyping call rate of 99.2%, and genotype imputation yielded over 3 million SNPs with an quality score greater than 0.90.

In the TGF-β pathway, the New Zealand AAA discovery GWAS identified a significant association in the transforming growth factor receptor III (TGFBR3) gene, also known as betaglycan. The minor A allele of the leading SNP rs11165595 in the TGFBR3 showed an increase in AAA risk in a recessive model (OR 1.39; 95% CI, 1.18-1.64; p = 9.1x10-6). Conflicting findings were observed when the association was validated in a secondary New Zealand AAA cohort. Genotyping analysis from additional international AAA studies showed consistent findings with the New Zealand discovery GWAS (OR 1.10; 95% CI, 1.04-1.17; p = 0.0017)

In the combined dyslipidemia/coronary artery disease pathway, the discovery GWAS identified twelve SNPs with significant associations with the risk of AAA. The genetic associations were investigated further in a secondary validation AAA cohort. The minor G allele of rs599839 in the 1p13 locus showed association with the risk of AAA (OR 0.75, 95% CI, 0.64-0.88; p = 1.8x10-4), despite its likely confounding effects on other cardiovascular conditions. The meta-analysis of this association with additional international AAA studies showed consistent observations (OR 0.83; 95% CI, 0.77-0.88; p = 3x10-9).

Conclusions:A genome-wide association study has been successfully conducted in the New Zealand AAA case-control cohort. Genetic associations identified in TGFBR3 and 1p13 loci suggested potential genetic predispositions in AAA. The pathway-based approach was shown to be a useful tool to uncover genetic associations with moderate effects, and this approach may be more appropriate to define AAA risk than a single SNP test. The findings in this study may provide a future direction for identifying more genetic variants contributing to the risk of AAA.